Human genetic polymorphisms influence the occurrence and evolution of HIV-1 infection. The goals of the Office of AIDS Research FY 2008 Plan for HIV-Related Research include the identification of host genetic factors that explain highly variable responses to the infection and its sequelae. This proposed initiative will provide new insight into key genetic determinants of these responses. This new knowledge will translate into guidance for vaccinologists grappling with the development of HIV vaccines and potential population differences in response to them, for biotechnologists pursuing strategies for immunomodulation of co-receptor and ligand molecules, and for clinicians designing and analyzing intervention trials. Genetic determinants will be studied primarily in infected and susceptible populations in Zambia, Uganda, and Rwanda and secondarily in European and African-American HIV/AIDS cohorts. Primary work will concentrate on a unique assembly of 1400 heterosexually active African couples who are discordant for HIV-1 infection (i.e., one partner HIV-1- positive and one negative). Through investigation of couples, responses of two hosts successively infected with related virus can be observed on a previously unequaled scale. This natural experiment permits powerful hypothesis testing for genetic effects on transmission and viral evolution in initially untreated individuals. Specific aims address genes in two pathways critical for the response to the virus. The first aim covers genes in the HLA class I antigen-presenting pathway (HLA-A, HLA-B and HLA-C) along with those in the leukocyte receptor complex (LRC) gene family including KIR genes and LILRB1 in the natural killer cell pathway. The second aim covers genes in the pathway for expression of the HIV-1 chemokine co-receptor and its ligands (CCR2, CCR5, CCL3, CCL3L1, CCL4, CCL4L1, and CCL5). Related new candidate genes will be considered. Public bioinformatics databases, genome-level sequencing services, and state-of-the-art laboratory techniques will be used to detect polymorphisms within the selected loci. Principal outcome measures include time to seroconversion in exposed HIV-1-negative partners and level of plasma viral RNA early in infection. Individual African cohorts will support independent hypothesis-testing, and powerful inferences may be drawn from data on judiciously aggregated cohorts. Analyses will emphasize predicted interactions between products of receptor and ligand genes. Simultaneous effects of multiple markers on outcomes will be examined. Comparisons effects across HIV-1 subtypes within Africans and across ethnic boundaries will be made. Through the application's innovative statistical approaches that take advantage of haplotype recognition, complex interactions and potential false discovery, a more comprehensive portrait of genetic determinants in HIV/AIDS will emerge. The carefully assembled phenotype data and specimen repository will also provide a solid infrastructure for further genetic/genomic research at the epidemiologic level and for collaborations with basic scientists aimed at probing the functional correlations of well-documented immunogenetic relationships. PROJECT NARRATIVE This genetic epidemiologic research on variants in key human immune response genes will help explain why individuals differ so widely in the ease with which they become infected with HIV and the rate at which they progress to disease. The knowledge is most directly relevant to the health of African populations. It will also translate into guidance for biomedical scientists who are grappling with the development of HIV vaccines and potential population differences in response to them, pursuing strategies for modulation molecules involved in viral entry into cells, and designing and analyzing intervention trials.